The invention relates to a phase and sedimentation-stable, plastically deformable preparation (implant material/bone replacement material) with intrinsic pore formation, that can be used for instance for filling bone defects and for augmentation, and also relates to a method for producing same.
Resorbable and non-resorbable implant materials based on calcium phosphates have been known for some time as bone replacement materials for filling bone defects and for augmentation. In addition to shaped bodies and granulates, in particular injectable and kneadable implant materials are of interest.
One method and composition for repairing bones is disclosed in WO 03/063686. The composition is a hydrogel that is formed from hyaluronic acid and that is mixed with animal bone components, bone-like powder, or hydroxyapatite. Likewise, a growth inducing peptide can be a component of the mixture.
A malleable bone composition for filling bone defects is described in EP 1 477 176 A1. This composition can be embodied as a paste or flowable gel and can comprise inter alia bone powder in a hydrogel carrier. In accordance with EP 1 477 176 A1, the powder component can comprise 25 to 35% of the material and can have a particle size of 100-850 μm. The hydrogel carrier can comprise chitosan having a molecular weight of 100,000-300,000 Daltons and comprising 1-4.5% of the material.
Known from U.S. Pat. No. 5,258,028 are injectable microimplants that comprise a hydrogel made of polyvinylpyrrolidone and a plastic material made of polydimethylsiloxane. Alternative to this polymer, particles made of calcium salts, such as hydroxyapatite, biocompatible ceramics, or biocompatible metals can also be used. The size of the biologically compatible particles can be between 10 and 3000 micrometers.
U.S. Pat. No. 4,713,076 discloses a coating composition that comprises highly porous spherical particles and a resorbable binder. The particles comprise tricalcium phosphate and the binder comprises gelatins, polyamino acids, or collagen.
U.S. Pat. No. 4,780,450 suggests a composition for bone treatment, the composition containing polycrystalline, particulate calcium phosphate ceramic, acid, phosphorous-containing proteins, and type I collagen. In U.S. Pat. No. 4,780,450, hydroxyapatite, β-tricalcium phosphate ceramic, or mixtures thereof are listed as calcium phosphate ceramics.
EP 0416 398 A1 also describes paste-like bone replacement material, the materials being formed from an aqueous solution of pullulan, glycol chitin, carboxymethyl chitin and pectin, in which solution calcium phosphate particles are suspended. Hydroxyapatite, fluorapatite, α-tricalcium phosphate, β-tricalcium phosphate, and tetracalcium phosphate are used as calcium phosphates.
US 2002/169506 also describes kneadable fill materials, these materials comprising calcium phosphate granulate and so-called “small chips”. These chips are formed from chitin and after contact with water are intended to bind the granules of the calcium phosphate granulate in that they stick together.
WO 03/082365 describes a kneadable and pliable bone replacement mass that comprises a mixture of calcium-containing ceramic particles and a hydrogel or a substance that can swell to form a hydrogel, the ceramic particles being of entirely synthetic origin and the majority of the ceramic particles not being round in shape. The individual ceramic particles have an at least partially cohesive, porous structure. The calcium-containing ceramic particles can comprise dicalcium phosphate dihydrate, dicalcium phosphate, α-TCP, β-TCP, wherein “TCP” means tricalcium phosphate, calcium-deficient hydroxyapatite, hydroxyapatite, carbonate apatite, chlorapatite, whitlockite, tetracalcium phosphate, oxyapatite, calcium pyrophosphate, and octacalcium phosphate. The substances that can swell to form hydrogels can contain polyamino acids, polysaccharides, polylipids, nucleotides, or combinations thereof as components.
Patent application US 2003/055512 discloses an injectable, bioresorbable bone replacement material based on calcium. The material is a mixture of calcium sulfate and a phosphate cement powder that hardens after mixing with water.
A paste for treating bones is known from WO 2004/011053. This paste comprises a carrier gel based on hyaluronic acid and synthetic hydroxyapatite suspended therein or comprises hydroxyapatite prepared from bone material.
“Bioresorbable composite bone paste using polysaccharide based nano hydroxyapatite” (R. Murugan, S. Ramakrishna, Biomaterials 2004, 25 3829-3835) describes a paste having nanoparticulate, precipitated hydroxyapatite. Sols made of chitosan, a polysaccharide, are used for binders and matrix for the hydroxyapatite particles.
FR 28 52 249 discloses a bone filling material, especially for use in conjunction with oral implants, comprising a source of phosphate and calcium and a stimulant for stimulating collagen production using osteoblasts, for instance in the form of hydroxyproline-mono or di-palmitate. Cited as calcium phosphate sources are hydroxyapatite, dicalcium phosphate, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, and octacalcium phosphate, which are intended to stimulate collagen formation. The composition can be produced in different forms, inter alia having a viscosity that permits application in a syringe.
The viscosity of the composition is set by means of cohesion promoters that belong to the group of celluloses, amidones, cyclodextrines, alginates, dextransul fates, polyvinylpyrrolidones, or hyaluronic acid. The grain size of the calcium phosphate is less than 100 μm and can be 50, 20, 10, or 5 μm. Combination with platelet rich plasma (PRP) and other growth factors is possible.
WO 03/035124 describes bioactive materials and methods for producing and using same. Disclosed in this publication inter alia is a bioactive composition made of a fibroin suspension and optionally a pore-forming, particulate material. The fibroin suspension can have the form of an occlusion, a gel, a crème, or a paste. The fibroin can derive from the fiber substance of silk threads from the Bombyx mori silkworm. The pore-forming, particulate material can be hydroxyapatite, tricalcium phosphate, Korelle, chitosan, or a combination of these materials. Furthermore, the pore-forming, particulate materials can be a composite in which the core can comprise calcium phosphates or glass ceramics and the surrounding shell can comprise one or a plurality of biodegradable polymers such as polylactide, polyglycolide, poly-alpha-hydroxy acids, polyamides, etc.
Known from WO 03/028779 is an injectable osseous defect filler comprising calcium salt particles, an organic binder having an affinity to the calcium salt, cells from the group of stem cells, osteogenic cells, and osteoprogenitor cells, and a pharmaceutically acceptable buffer. In this osseous filler, calcium phosphate particles, such as for instance monetite (CaHPO4), brushite (CaHPO4*2H2O), calcium pyrophosphate, and also calcium carbonate and combinations thereof are used as calcium salts. The calcium salts can also comprise hydroxyapatite and β-TCP or mixtures thereof. The particle diameter of the calcium salts is in the range of 100 to 600 μm, preferably in the range of 200 to 400 μm. Alginates, dextrans, celluloses and their derivatives, plasma, biogenic binders, hyaluronic acid and combinations thereof are cited as organic binders. Hyaluronic acid, sodium alginate, sodium carboxymethyl cellulose, dextran, fibrin glue, and transglutaminase are preferred. WO 03/028779 states that the best effects are obtained with sodium alginate. In accordance with this publication, the quantities of binder are in the range of 0.5 to 10% by weight, preferably in the range of 3 to 7% by weight. A phosphate buffer (PBS) is used for the buffer. The solid content is in the range of 30 to 70, preferably in the range of 40 to 60% by weight. According to WO 03/028779, pastes having a viscosity of 30,000 to 100,000 centipoise can be easily injected. The needles used have a diameter of 2 to 5 mm and a length of 5 to 20 mm. The information regarding the force necessary for injection is provided as a function of different parameters. Additional growth factors may be present in addition to the cells that colonize on the surface of the calcium phosphate particles.
Known from WO 02/058755 is an injectable porous bone replacement material that can increase its porosity in situ. This material comprises a bone-like compound and a hydrophobic carrier. The bone-like compound can comprise calcium phosphates, potassium phosphate, calcium sulfate, hydroxyapatite, bioactive glasses, and combinations thereof. The hydrophobic substances can comprise proteins, glycoproteins, polyesters, polyanhydrides, polyamines, wax-like biodegradable polymers such as polyglycolid and combinations thereof.
Moreover, in accordance with WO 02/058755, aqueous components and mixtures of a degradable component and the aforesaid bone-like substances can be used. The biodegradable components can comprise polyhydroxypolyesters, albumin, collagen, proteins, polysaccharides, glycoproteins, and combinations thereof. A gas forming component, for instance hydrogen peroxide and/or peroxidase, is suggested for producing porosity.
WO 01/41821 describes an injectable, self-setting mixture that enables formation of hardened biomaterials with broad variations in properties. This mixture comprises a water-based liquid component, at least one cationic polymer, and a monophosphate salt having a pH in the range of 6.5 to 7.4. According to WO 01/41821, the aqueous phase has endothermal gel-forming properties. The second component of the mixture comprises at least two calcium phosphates made of apatites, octacalcium phosphates, amorphous calcium phosphates, tetracalcium phosphates, tricalcium phosphates, dicalcium phosphates, and monocalcium phosphates. The cationic polymer is contained in the first component at 0.1-5.0% by weight and can comprise polysaccharides, polypeptides or synthetic polymers, chitin, or chitosan. The monophosphate salt can constitute sodium potassium phosphates, magnesium phosphates, manganese phosphates, or iron phosphates with different stoichiometry. Mentioned as water-soluble polymers are various modified celluloses, polyethylene glycol, polyvinyl alcohol, organic polyols, glycol oligomers, sugar, and glycerol. The mixture can furthermore contain growth factors.
EP 1 475 109 A1 discloses a formulation for injectable application of osteogenic proteins comprising a pharmaceutically acceptable admixture of the osteogenic protein and a hemostatic gelatin foam paste. This formulation can also contain tricalcium phosphate. The osteogenic proteins can derive from the BMP (bone morphogenetic protein) family, preferably BMP-2 and OP-1. The TCP (tricalcium phosphate) particles are microporous and have a particle size of 45-125 μm, which can be injected through an 18-gauge needle (equivalent of 1.2 mm diameter and 40 mm length). Moreover, this publication also describes alginates or celluloses as agents for controlled release of the proteins.
Known from WO 01/41824 is a hydraulic brushite cement that is stabilized with magnesium salts. The brushite cement can be produced from an basic calcium phosphate, a second component comprising an acid calcium phosphate, a third component comprising water, and a fourth component, for controlling the setting reaction, comprising a magnesium salt. In accordance with WO 01/41824, the basic calcium phosphates can derive from the class of tricalcium phosphates and apatites. The acid phosphate components can comprise monocalcium phosphates. The fourth component, contained as from 0.001 to 60% by weight, can derive from various magnesium phosphates and magnesium salts of organic compounds.
The liquid components can also contain sulfuric acid or phosphoric acid. In accordance with WO 01/41824, additives can be used for controlling the flow properties of the cements. These can comprise polysaccharides, preferably hyaluronic acid and its salts, dextran, alginate, hydroxypropylmethyl cellulose, chitosan, or xanthan. The cement can contain granules with diameters ranging from 100 μm to 500 μm, preferably ranging from 200 to 350 μm. The granules can comprise calcium phosphate or gypsum. The set cement mixture can have a Ca:P ratio of 1.00 to 1.67.
WO 00/07639 discloses bone precursor compositions and methods for producing same. These compositions can contain injectable calcium cements made of monocalcium phosphate monohydrate and β-TCP (“TCP” meaning tricalcium phosphate) and also calcium pyrophosphate and calcium sulfate. These calcium cements can have granular shapes ranging from 1 to 500 μm. Collagens, methylcellulose, biopolymers, or other pharmaceutically acceptable substances may be contained for controlling viscosity. In addition, CAPS, triethanolamine, TES, tricine, HEPES, glycine, PBS, bis tris propane, TAPS, AMP, and TRIS can be used to neutralize the pH of the bone precursor substance.
WO 00/45867 discloses a hydraulic cement having a calcium source, water, and a hydrophobic liquid. This mixture constitutes a calcium source and water, which when mixed with one another results in a self-hardening cement paste. A third component comprises a hydrophobic liquid that, washed out in situ, results in a cement having an open macroporosity that permits rapid bone ingrowth. The hydrophobic liquid can derive from the group of fats or oils. The calcium source can derive from the class of calcium phosphates. The Ca:P ratio for the calcium source can be between 1.0 and 1.67. In this regard, the publication cites inter alia monocalcium phosphate monohydrate and anhydrous monocalcium phosphate, dicalcium phosphate, octacalcium phosphate, alpha and beta tricalcium phosphate, tetracalcium phosphate, hydroxyapatite. Polymer additives can be used as additives for controlling the flow properties of the cement. These additives can derive from the group of polysaccharides and can include for instance modified celluloses such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and hyaluronic acid. Moreover, an emulsifying agent from the group of surfactants can be used as a stabilizer. Pharmaceutically and physiologically active substances can be added in.
Known from WO 95/21634 is a biomaterial composition and a method for producing same. The composition can contain 40 to 75% by weight β-tricalcium phosphate and hydroxyapatite in a ratio of from 20:80 to 70:30, as well as calcium titanium phosphate (CaTi4(PO4)6) and 60 to 25% by weight of a liquid phase, comprising an aqueous solution of a cellulose derivative. Furthermore, the publication also mentions hydroxypropyl methylcellulose.
The size of the granules is 80 to 200 μm. The material is sterile, ready for use, and injectable.